The present invention relates to novel compounds, the use of these compounds as medicaments, the use of these medicaments in the treatment of and/or prevention of diabetes, and especially non-insulin dependent diabetes (NIDDM or Type 2 diabetes) including overnight or meal treatment and treatment or prevention of long-term complications, such as retinopathy, neuropathy, nephropathy, and micro- and macroangiopathy; treatment of hyperglycemia, hyperchloesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or ischemia or treatment or prophylaxis of obesity or appetite regulation, pharmaceutical compositions containing these compounds and methods of preparing the compounds.
Diabetes is characterized by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups: Type 1 diabetes, or insulin demanding diabetes mellitus (IDDM), which arises when patients lack xcex2-cells producing insulin in their pancreatic glands, and Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with an impaired xcex2-cell function besides a range of other abnormalities.
Type 1 diabetic patients are currently treated with insulin, while the majority of Type 2 diabetic patients are treated either with sulphonylureas that stimulate xcex2-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin or with insulin. Among the agents applied to enhance tissue sensitivity towards insulin metformin is a representative example.
Even though sulphonylureas are widely used in the treatment of NIDDM this therapy is, in most instances, not satisfactory: In a large number of NIDDM patients sulphonylureas do not suffice to normalise blood sugar levels and the patients are, therefore, at high risk for acquiring diabetc complications. Also, many patients gradually lose the ability to respond to treatment with sulphonylureas and are thus gradually forced into insulin treatment. This shift of patients from oral hypoglycaemic agents to insulin therapy is usually ascribed to exhaustion of the xcex2-cells in NIDDM patients.
In normal subjects as well as in diabetic subjects, the liver produces glucose in order to avoid hypoglycaemia. This glucose production is derived either from the release of glucose from glycogen stores or from gluconeogenesis, which is a de novo intracellular synthesis of glucose. In Type 2 diabetes, however, the regulation of hepatic glucose output is poorly controlled and is increased, and may be doubled after an overnight fast. Moreover, in these patients there exists a strong correlation between the increased fasting plasma glucose levels and the rate of hepatic glucose production (reviewed in R. A. De Fronzo: Diabetes 37, 667-687 (1988); A. Consoli: Diabetes Care 15, 430-441 (1992); and J. E. Gerich: Horm.Metab.Res. 26, 18-21 (1992)). Similarly, hepatic glucose production will be increased in Type 1 diabetes, if the disease is not properly controlled by insulin treatment.
Since existing forms of therapy of diabetes does not lead to sufficient glycaemic control and therefore are unsatisfactory, there is a great demand for novel therapeutic approaches. Since the liver in diabetes is known to have an increased glucose production, compounds inhibiting this activity are highly desirable. Recently, patent applications on inhibitors of the liver specific enzyme, glucose-6-phosphatase, which is necessary for the release of glucose from the liver, have been filed, for example DE-A-4,202,183, DE-A-4,202,184, WO98/40385, WO99/40062, and JP-A-4-58565.
Substituted N-(indole-2-carbonyl)-glycinamides acting as glycogen phosphorylase inhibitors are disclosed in WO96/39384, WO96/39385 and in EP-A-0 846 464. Piperidine and pyrrolidine compounds acting as glycogen phosphorylase inhibitors are disclosed in WO95/24391, WO 97/09040, WO 98/40353, and WO 98/50359.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. The earliest stage in this sequence is the formation of xe2x80x9cfatty streaksxe2x80x9d in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in colour due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the chloesterol found within the fatty streaks, in turn, give rise to development of the xe2x80x9cfibrous plaquexe2x80x9d, which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified chloesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the xe2x80x9ccomplicated lesionxe2x80x9d which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma chloesterol levels, and low density lipoprotein chloesterol in particular, as an essential step in prevention of CVD. The upper limits of xe2x80x9cnormalxe2x80x9d are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particular high risk. Independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
Hypertension (or high blood pressure) is a condition, which occurs in the human population as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma, or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent or disorder is unknown. While ushc xe2x80x9cessentialxe2x80x9d hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia, the relationship between these disorders has not been elucidated. Additionally, many patients display the symptoms of high blood pressure in the complete absence of any other signs of disease or disorder.
It is know that hypertension can directly lead to heart failure, renal failure, and stroke (brain haemorrhaging). These conditions are capable of causing short-term death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken a patient and can lead to long-term death.
The exact cause of essential hypertension is unknown, though a number of factors are believed to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin aldosterone system), excessive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vasculature resulting in constricted blood vessels and genetic factors.
The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus a broad range of beta-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure, and brain haemorrhaging. However, the development of atherosclerosis or heart disease due to hypertension over a long period of time remains a problem. This implies that although high blood pressure is being reduced, the underlying cause of essential hypertension is not responding to this treatment.
Hypertension has been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also acts to promote vascular cell growth and increase renal sodium retention, among other things. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries, while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby alleviates hypertension.
Cardiac hypertrophy is a significant risk factor in the development of sudden death, myocardial infarction, and congestive heart failure. These cardiac events are due, at least in part, to increased susceptibility to myocardial injury after ischemia and reperfusion, which can occur in out-patient as well as perioperative settings. There is an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both non-cardiac and cardiac surgery are associated with substantial risks for myocardial infarction or death. Some 7 million patients undergoing non-cardiac surgery are considered to be at risk, with incidences of perioperative death and serious cardiac complications as high as 20-25% in some series. In addition, of the 400,000 patients undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to occur in 5% and death in 1-2%. There is currently no drug therapy in this area, which reduces damage to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resistance to ischemic episodes. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Another field for the present invention is obesity or appetite regulation.
Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension, and diabetes. The incidence of obese people and thereby also these diseases is increasing throughout the entire industrialised world. Except for exercise, diet and food restriction no convincing pharmacological treatment for reducing body weight effectively and acceptably currently exist. However, due to its indirect but important effect as a risk factor in mortal and common diseases it will be important to find treatment for obesity and/or means of appetite regulation.
The term obesity implies an excess of adipose tissue. In this context obesity is best viewed as any degree of excess adiposity that imparts a health risk. The cut off between normal and obese individuals can only be approximated, but the health risk imparted by the obesity is probably a continuum with increasing adiposity. The Framingham study demonstrated that a 20% excess over desirable weight clearly imparted a health risk (Mann G V N.Eng.J.Med 291:226, 1974). In the United States a National Institutes of Health consensus panel on obesity agreed that a 20% increase in relative weight or a body mass index (BMI=body weight in kilograms divided by the square of the height in meters) above the 85th percentile for young adults constitutes a health risk. By the use of these criteria 20 to 30 percent of adult men and 30 to 40 percent of adult women in the United State are obese. (NIH, Ann Intern Med 103:147, 1985).
Even mild obesity increases the risk for premature death, diabetes, hypertension, atherosclerosis, gallbladder disease, and certain types of cancer. In the industrialised western world the prevalence of obesity has increased significantly in the past few decades. Because of the high prevalence of obesity and its health consequences, its prevention and treatment should be a high public health priority.
When energy intake exceeds expenditure, the excess calories are stored in adipose tissue, and if this net positive balance is prolonged, obesity results, i.e. there are two components to weight balance, and an abnormality on either side (intake or expenditure) can lead to obesity.
The regulation of eating behaviour is incompletely understood. To some extent appetite is controlled by discrete areas in the hypothalamus: a feeding centre in the ventrolateral nucleus of the hypothalamus (VLH) and a satiety centre in the ventromedial hypothalamus (VMH). The cerebral cortex receives positive signals from the feeding centre that stimulate eating, and the satiety centre modulates this process by sending inhibitory impulses to the feeding centre. Several regulatory processes may influence these hypothalamic centres. The satiety centre may be activated by the increases in plasma glucose and/or insulin that follow a meal. Meal-induce gastric distension is another possible inhibitory factor. Additionally the hypothalamic centres are sensitive to catecholamines, and beta-adrenergic stimulation inhibits eating behaviour. Ultimately, the cerebral cortex controls eating behaviour, and impulses from the feeding centre to the cerebral cortex are only one input. Psychological, social, and genetic factors also influence food intake.
At present a variety of techniques are available to effect initial weight loss. Unfortunately, initial weight loss is not an optimal therapeutic goal. Rather, the problem is that most obese patients eventually regain their weight. An effective means to establish and/or sustain weight loss is the major challenge in the treatment of obesity today.
Thus there remains today a need in the art for compositions and methods that are useful for the treatment or prophylaxis of obesity or appetite regulation.
One object of the present invention is to provide compounds that can be used as medicaments for treatment of one or more of the above-mentioned diseases and disorders.
A further object of this invention is to provide compounds that can effectively be used in the treatment of diabetes, preferably Type 2 diabetes, including overnight or meal treatment and preferably for treatment of increased plasma glucose levels.
A still further object of this invention is to provide compounds that can effectively be used as inhibitors of glucose production from the liver.
A still further object of this invention is to provide compounds that can be effectively used as glycogen phosphorylase inhibitors.
It has now been found that members of a novel group of aromatic compounds with formula I have interesting pharmacological properties. For example, the compounds of this invention can be used in the treatment of diabetes. Especially, the compounds of this invention are active as inhibitors of glucose production from the liver. Consequently, the compounds of this invention can be used for the treatment of the increased plasma glucose levels in diabetics.
Accordingly, it is an object of the present invention to provide such novel compounds.
Further objects will become apparent from the following description.
The present invention relates to novel compounds of the general formula I 
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or pharmaceutically acceptable basic organic or inorganic addition salts or hydrates or prodrugs thereof, wherein
A is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94,  greater than SO,  greater than SO2,  greater than CO,  greater than CR9R10, or  greater than NR11;
R1 and R2 independently are one of the following groups: hydrogen, CN, xe2x80x94C(O)NR6R7, xe2x80x94COOH, xe2x80x94PO(OH)2, xe2x80x94SO2OH, tetrazole, 1-hydroxy-1,2-diazole, 1-hydroxytriazole, 1-hydroxyimidazole, 2-hydroxytriazole, or 1-hydroxytetrazole; when R1 or R2 is hydrogen, the other of R1 and R2 is xe2x80x94PO(OH)2 or xe2x80x94SO2OH; or R1 and R2 together may form an anhydride or an imide;
R3 and R4 independently are C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, or C3-8-cycloalkyl, each optionally substituted with halogen, hydroxy, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, xe2x80x94NR6R7, xe2x80x94NHCOR7, C1-8-alkoxy, NO2, trifluoromethoxy, carbamoyl, or xe2x80x94CONR6R7; or R3 and R4 independently are hydrogen, halogen, perhalomethyl, C1-8-alkoxy, C1-8-alkylthio, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, trifluoromethoxy, xe2x80x94SO2OH, xe2x80x94PO(OH)2, xe2x80x94COOR6, xe2x80x94CN, hydroxy, xe2x80x94OCOR6, xe2x80x94NR6R7, xe2x80x94NHCOR7, xe2x80x94COC1-8-alkyl, xe2x80x94CONR6R7, xe2x80x94CONHSO2R7, xe2x80x94SO2NHR7, NO2, C1-8alkoxycarbonyl, aryl, heteroaryl, C1-8-alkylphenyl, or tetrazole;
R5 is xe2x80x94COxe2x80x94R8, xe2x80x94CH2xe2x80x94R8, or xe2x80x94CSxe2x80x94R8; wherein R8 is aryl, C1-8alkyl, C2-8-alkene, phenyl-C1-8alkyl, heteroaryl, or C3-8-cycloalkyl, each optionally substituted with one or more substituents selected from halogen, hydroxy, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NR6R7, xe2x80x94NYCOR7, C1-8-alkyl, C1-8-alkoxy, perhalomethoxy, carbamoyl, xe2x80x94CONR6R7, perhalomethyl, xe2x80x94OCOR6, xe2x80x94COxe2x80x94R6, xe2x80x94OR6, C1-8-alkylthio, xe2x80x94COOR6, xe2x80x94SO2OH, xe2x80x94SO2CH3, xe2x80x94PO(OH)2, xe2x80x94CN, xe2x80x94NHCOR7, xe2x80x94CONHSO2R7, xe2x80x94SO2NHR7, C1-8-alkoxycarbonyl, and tetrazole; wherein
R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, phenyl-C1-8-alkyl or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, NH2, NO2, xe2x80x94NH(C1-8-alkyl), xe2x80x94N(C1-8-alkyl)2, xe2x80x94NHCO(C1-8-alkyl), C1-8-alkoxy, and trifluoromethoxy;
R9 and R10 independently are hydrogen, hydroxy, SH, halogen, or C1-8-alkyl; and
R11 is hydrogen, C1-8-alkyl, -carbonyl(C1-8-alkyl), or phenyl-C1-8-alkyl.
In one embodiment of the present invention A is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, preferably A is xe2x80x94Oxe2x80x94.
In a second embodiment of the present invention R1 and R2 both are xe2x80x94COOH or CN, preferably xe2x80x94COOH or R1 and R2 together form an imide.
In a third embodiment of the present invention R3 is hydrogen.
In a further embodiment of the present invention R4 is hydrogen.
In one embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl, C1-8-alkyl, C2-8-alkene, phenyl-C1-8alkyl, heteroaryl, or C3-8-cycloalkyl, each optionally substituted with one or more substituents selected from halogen, hydroxy, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NR6R7, xe2x80x94NHCOR7, C1-8-alkyl, C1-8-alkoxy, perhalomethoxy, carbamoyl, xe2x80x94CONR6R7, perhalomethyl, xe2x80x94OCOR6, xe2x80x94COxe2x80x94R6, xe2x80x94OR6, C1-8alkylthio, xe2x80x94COOR6, xe2x80x94SO2OH, xe2x80x94PO(OH)2, xe2x80x94CN, xe2x80x94NHCOR7, xe2x80x94CONHSO2R7, xe2x80x94SO2NHR7, C1-8-alkoxycarbonyl, and tetrazole; wherein R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, phenyl-C1-8-alkyl or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, NH2, NH(C1-8-alkyl), N(C1-8-alkyl(2, NHCO(C1-8-alkyl), C1-8-alkoxy, and trifluoromethoxy.
In a second embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl or hetereoaryl, each optionally substituted with one or more substituents selected from halogen, hydroxy, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NR6R7, xe2x80x94NHCOR7, C1-8-alkyl, C1-8-alkoxy, perhalomethoxy, carbamoyl, xe2x80x94CONR6R7, perhalomethyl, xe2x80x94OCOR6, xe2x80x94COxe2x80x94R6, xe2x80x94OR6, C1-8-alkylthio, xe2x80x94COOR6, xe2x80x94SO2OH, xe2x80x94PO(OH)2, CN, xe2x80x94NHCOR7, xe2x80x94CONHSO2R7, xe2x80x94SO2NHR7, C1-8-alkoxycarbonyl, and tetrazole; wherein R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, phenyl-C1-8-alkyl or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, NH2, xe2x80x94NH(C1-8-alkyl), xe2x80x94N(C1-8-alkyl)2, xe2x80x94NHCO(C1-8-alkyl), C1-8-alkoxy, and trifluoromethoxy.
In a third embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents selected from halogen, hydroxy, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NR6R7, xe2x80x94NHCOR7, C1-8-alkyl, C1-8-alkoxy, perhalomethoxy, carbamoyl, xe2x80x94CONR6R7, perhalomethyl, xe2x80x94OCOR6, xe2x80x94COxe2x80x94R6, xe2x80x94OR6, C1-8-alkylthio, xe2x80x94COOR6, xe2x80x94SO2OH, xe2x80x94PO(OH)2, CN, xe2x80x94NHCOR7, xe2x80x94CONHSO2R7, xe2x80x94SO2NHR7, C1-8-alkoxycarbonyl, and tetrazole; wherein R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, phenyl-C1-8-alkyl or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, NH2, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NH(C1-8-alkyl), xe2x80x94N(C1-8-alkyl)2, xe2x80x94NHCO(C1-8-alkyl), C1-8-alkoxy, and trifluoromethoxy.
In a further embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents selected from halogen, COOR6, NO2, xe2x80x94SO2CH3, CN, C1-8-alkyl (preferably methyl, tert-butyl, isopropyl, pentyl, heptyl), perhalomethyl (preferably trifluoromethyl), C1-8-alkoxy (preferably methoxy or ethoxy), perhalomethoxy (preferably trifluoromethoxy), C1-8-alkylthio (preferably methylthio), xe2x80x94COxe2x80x94R6, xe2x80x94NR6R7, xe2x80x94NHxe2x80x94COxe2x80x94R7, and xe2x80x94OR6; wherein R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, phenyl-C1-8--alkyl or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, NH2, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NH(C1-8-alkyl), xe2x80x94N(C1-8alkyl)2, xe2x80x94NHCO(C1-8alkyl), C1-8-alkoxy, and trifluoromethoxy.
In a still further embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents and at least one of the substituents is COOH.
In a still further embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents and at least one of the substituents is NO2.
In a still further embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents and at least one of the substituents is halogen (preferably bromo or chloro).
In a further embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) substituted with one or more substituents and at least one of the substituents is xe2x80x94COxe2x80x94R6, wherein R6 is C1-8-alkyl (preferably CH3) or substituted aryl (preferably phenyl) substituted with halogen or substituted with C1-8-alkyl (preferably CH3).
In one embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) substituted with one or more substituents and at least one of the substituents is xe2x80x94NH-xe2x80x94COxe2x80x94R7, wherein R7 is C1-8-alkyl (preferably CH3).
In a second embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) substituted with one or more substituents and at least one of the substituents is xe2x80x94NR6R7, wherein R6 and R7 independently are hydrogen or C1-8-alkyl (preferably CH3).
In a third embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is phenyl substituted with one or more substituents and at least one of the substituents is xe2x80x94OR6, wherein R6 is C1-8-alkyl (preferably methyl).
In a further embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is benzo[1,3]dioxole, 2,3-dihydrobenzofuran, or benzofuran, each optionally substituted with one or more substituents selected from halogen, C1-8-alkyl (preferably methyl), and C1-8-alkoxy (preferably methoxy).
The present invention relates also to novel compounds of the general formula Ia 
wherein
R1 and R2 independently are one of the following groups: hydrogen, CN, xe2x80x94C(O)NR6R7, xe2x80x94COOH, xe2x80x94PO(OH)2, xe2x80x94SO2OH, tetrazole, 1-hydroxy-1,2-diazole, 1-hydroxytriazole, 1-hydroxyimidazole, 2-hydroxytriazole, 1-hydroxytetrazole; when R1 or R2 is hydrogen, the other of R1 and R2 is xe2x80x94PO(OH)2 or xe2x80x94SO2OH; or R1 and R2 together may form an anhydride or an imide;
R5 is xe2x80x94COxe2x80x94R8, xe2x80x94CH2xe2x80x94R8, or xe2x80x94CSxe2x80x94R8; wherein R8 is aryl, C1-8-alkyl, C2-8-alkene, phenyl-C1-8-alkyl, hetereoaryl, or C3-8-cycloalkyl, each optionally substituted with one or more substituents selected from halogen, hydroxy, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NR6R7, xe2x80x94NHCOR7, C1-8-alkyl, C1-8-alkoxy, perhalomethoxy, carbamoyl, xe2x80x94CONR6R7, perhalomethyl, xe2x80x94OCOR6, xe2x80x94COxe2x80x94R6, xe2x80x94OR6, C1-8-alkylthio, xe2x80x94COOR6, xe2x80x94SO2OH, xe2x80x94PO(OH)2, xe2x80x94CN, xe2x80x94NHCOR7, xe2x80x94CONHSO2R7, xe2x80x94SO2NHR7, C1-8-alkoxycarbonyl, and tetrazole;
wherein R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, phenyl-C1-8-alkyl, or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, NH2, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NH(C1-8-alkyl), xe2x80x94N(C1-8-alkyl)2, xe2x80x94NHCO(C1-8-alkyl), C1-8-alkoxy, and trifluoromethoxy.
In a preferred embodiment of the present invention R1 and R2 are xe2x80x94COOH.
In another preferred embodiment of the present invention R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl, C1-8-alkyl, C2-8-alkene, phenyl-C1-8-alkyl, hetereoaryl, or C3-8-cycloalkyl, each optionally substituted with one or more substituents selected from halogen, hydroxy, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NR6R7, xe2x80x94NHCOR7, C1-8-alkyl, C1-8-alkoxy, perhalomethoxy, cabamoyl, xe2x80x94CONR6R7, perhalomethyl, xe2x80x94OCOR6, xe2x80x94COxe2x80x94R6, xe2x80x94OR6, C1-8-alylthio, xe2x80x94COOR6, xe2x80x94SO2OH, xe2x80x94PO(OH)2, xe2x80x94CN, xe2x80x94NHCOR7, xe2x80x94CONHSO2R7, xe2x80x94SO2NHR7, C1-8-alkoxycarbonyl, and tetrazole; wherein R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, phenyl-C1-8-alkyl or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, NH2, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NH(C1-8-alkyl), xe2x80x94N(C1-8-alkyl)2, xe2x80x94NHCO(C1-8alkyl), C1-8-alkoxy, and trifluoromethoxy.
The present invention also relates to novel compounds of the general formula Ib 
wherein R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl, C1-8-alkyl, C2-8-alkene, phenyl-C1-8-alkyl, heteroaryl, or C3-8-cycloalkyl, each optionally substituted with one or more substituents selected from halogen, hydroxy, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NR6R7, xe2x80x94NHCOR7, C1-8-alkyl, C1-8-alkoxy, perhalomethoxy, carbamoyl, xe2x80x94CONR6R7, perhalomethyl, xe2x80x94OCOR6, xe2x80x94COxe2x80x94R6, xe2x80x94OR6, C1-8-alkylthio, xe2x80x94COOR6, xe2x80x94SO2OH, xe2x80x94PO(OH)2, xe2x80x94CN, xe2x80x94NHCOR7, xe2x80x94CONHSO2R7, xe2x80x94SO2NHR7, C1-8-alkoxycarbonyl, and tetrazole; wherein
R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, pheny-C1-8-alkyl, or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, NH2, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NH(C1-8-alkyl), xe2x80x94N(C1-8-alkyl)2, xe2x80x94NHCO(C1-8-alkyl), C1-8-alkoxy, and trifluoromethoxy.
Preferably R5 is xe2x80x94COxe2x80x94R8, wherein R8 is aryl (preferably phenyl) optionally substituted with one or more substituents selected from halogen, COOR6, NO2, xe2x80x94SO2CH3, CN, C1-8-alkyl (preferably methyl, tertbutyl, isopropyl, pentyl, heptyl), perhalomethyl (preferably trifluoromethyl), C1-8-alkoxy (preferably methoxy or ethoxy), perhalomethoxy (preferably trifluoromethoxy), C1-8-alkylthio (preferably methylthio), xe2x80x94COxe2x80x94R6, xe2x80x94NR6R7, xe2x80x94NHxe2x80x94COxe2x80x94R7, and xe2x80x94OR6; wherein
R6 and R7 independently are hydrogen, C1-8-alkyl, aryl, phenyl-C1-8-alkyl or heteroaryl, each optionally substituted with one or more substituents selected from halogen, OH, NH2, xe2x80x94SH, xe2x80x94SOR6, xe2x80x94SO2R6, NO2, xe2x80x94NH(C1-8-alkyl), xe2x80x94N(C1-8-alkyl)2, xe2x80x94NHCO(C1-8-alkyl), C1-8-alkoxy, and trifluoromethoxy.
Preferred compounds of the present invention are:
4-[2-(3-dimethylaminobenzoylamino)phenoxy]phthalic acid, 4-[2-(3-dimethylaminobenzoyl-amino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-iodobenzoylamino)phenoxy]phthalic acid, 4-[2-(3-iodobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[2-(2-fluoro-5-trifluoromethylbenzoylamino)phenoxy]phthalic acid, 4-[2-(2-fluoro-5-trifluoromethylbenzoyl-amino)phenoxy]phthalic acid dimethyl ester, 4-[2-(2-fluorobenzoylamino)phenoxy]phthalic acid, 4-[2-(2-fluorobenzoylamino)phenoxy]phthalic cid dimethyl ester, 4-[2-(3-acetylbenzoyl-amino)phenoxy]phthalic acid, 4-[2-(3-acetylbenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-bromobenzoylamino)phenoxy]phthalic acid, 4-[2-(3-bromobenzoylamino)-phenoxy]phthalic acid dimethyl ester, 4-[2-(3-chlorobenzoylamino)phenoxy]phthalic acid 4-[2-(3-chlorobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[2-(2,3-difluorobenzoyl-amino)phenoxy]phthalic acid, 4-[2-(2,3-difluorobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[2-(2,4-difluorobenzoylamino)phenoxy]phthalic acid, 4-[2-(2,4-difluorobenzoylamino)-phenoxy]phthalic acid dimethyl ester, 4-[2-(2,5-difluorobenzoylamino)phenoxy]phthalic aicd, 4-[2-(2,5-difluorobenzoylamino)phenoxy]phthalic aicd dimethyl ester, 4-[2-(4-fluorobenzoyl-amino)phenoxy]phthalic acid, 4-[2-(4-fluorobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-(2-benzoylaminophenoxy)phthalic acid, 4-(2-benzoylaminophenoxy)phthalic acid dimethyl ester, 4-[2-(3-methylbenzoylamino)phenoxy]phthalic acid, 4-[2-(3-methylbenzoyl-amino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-cyanobenzoylamino)phenoxy]phthalic acid, 4-[2-(3-cyanobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[4-amino-2-(3-nitro-benzoylamino)phenoxy]phthalic acid, 4-[4-amino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester, N-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yloxy)phenyl]-3-nitrobenz-amide, 4-[2-(3-aminobenzoylamino)phenoxy]phthalic acid 4-[2-(3-aminobenzoylamino)-phenoxy]phthalic acid dimethyl ester, 4-[4-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[4-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-nitrobenzoylamino)-phenylsulphenyl]phthalic acid, 4-[2-(3-nitrobenzoylamino)phenylsulphenyl]phthalic acid dimethyl ester, 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[2-(3-nitrobenzoylamino)-phenoxy]phthalic acid dimethyl ester, 4-[4-(4-iodobenzoylamino)-2-(3-nitrobenzoylamino)-phenoxy]phthalic acid, 4-[4-(4-iodobenzoylamino)-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[4-methoxycarbonyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[4-methoxycarbonyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester 4-[4-acetylamino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[4acetylamino-2-(3-nitro-benzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[5-fluoro-2-(3-nitrobenzoylamino)-phenoxy]phthalic aicd, 4-[5-fluoro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[4-bromo-2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[4-bromo-2-(3-nitro-benzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[4-benzoylamino-2-(3-nitrobenzoyl-amino)phenoxy]phthalic acid, 4-[4-benzoylamino-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[5-methyl-2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[5-methyl-2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic aicd dimethyl ester, 4-[4-cyano-2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[4-cyano-2-(3-nitrobenzoylamino)phenoxy]-phthalic acid dimethyl ester, 4-[4,5-dichloro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[4,5-dichloro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[5-bromo-4-fluoro-2-(3-nitrobenzoylamino)phenoxy]phthalic acid, (4-[5-bromo-4-fluoro-2-(3-nitrobenzoyl-amino)phenoxy]phthalic acid dimethyl ester, 4-[4-methyl-2-(3-nitrobenzoylamino)phenoxy]-phthalic acid, 4-[4-methyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[4-fluor-2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[4-fluoro-2-(3-nitrobenzoylamino)-phenoxy]phthalic acid dimethyl ester, 4-[5-methyl-2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[5-methyl-2-(3-nitrobenzoylamino)phenoxy]phthalic aicd dimethyl ester, 4-[2-(3-nitro-benzoylamino)-4-trifluoromethylphenoxy]phthalic acid, 4-[2-(3-nitrobenzoylamino)-4-trifluoro-methylphenoxy]phthalic acid dimethyl ester, 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]-phthalic acid, 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-nitrobenzoylamino)benzyl]phthalic acid, 4-[2-(3-nitrobenzoylamino)benzyl]phthalic acid dimethyl ester, 4-[2-(3-fluorobenzoylamino)phenoxy]phthalic acid, 4-[2-(3-fluorobenzoyl-amino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-trifluoromethylbenzoylamino)phenoxy]-phthalic acid, 4-[2-(3-trifluoromethylbenzoylamino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-nitrobenzylamino)phenoxy]phthalic acid, 4-[2-(3-nitrobenzylamino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-trifluoromethoxybenzoylamino)phenoxy]phthalic acid, 4-[2-(3-trifluoro-methoxybenzoylamino)phenoxy]phthalic acid dimethyl ester, 4{benzyl-[2-(3nitrobenzoyl-amino)phenyl]amino}phthalic acid, 4{benzyl-[2-(3-nitrobenzoylamino)phenyl]amino}phthalic acid dimethyl ester, 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid, 4-[2-(3-nitrobenzoyl-amino)phenoxy]phthalic acid dimethyl ester, 4-[2-(3-methoxybenzoylamino)phenoxy]phthalic acid, and 4-[2-(3-methoxybenzoylamino)phenoxy]phthalic acid dimethyl ester.
The compounds of the present invention may have one or more asymmetric centers and it is intended that steroisomers (optical isomers), as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the present invention.
Within the present invention, the compounds of formula I, Ia or Ib may optionally be prepared in the form of pharmaceutically acceptable basic salts or mixtures thereof, as pharmaceutically acceptable metals salts orxe2x80x94optionally alkylatedxe2x80x94ammonium salts.
Examples of such salts include inorganic and organic basic addition salts and the like, and include bases related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science 66, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like. The compounds of formula I, Ia or Ib may be administered in pharmaceutically acceptable basic addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free acid forms.
Also intended as pharmaceutically acceptable addition salts are the hydrates, which the present compounds are able to form.
The basic addition salts may be obtained s the direct products of compound synthesis. In the alternative, the free acid may be dissolved in a suitable solvent containing the appropriate base, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan. Such solvates are also contamplated as being within the scope of the present invention.
The present invention relates to a compound of the above general formula I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof or any optical isomer thereof or a mixture of optical isomers, including a racemic mixture, or any tautomeric form thereof for use as a medicament.
The present invention relates to a pharmaceutical composition comprising, as an active ingredient, an effective amount of a compound of the above general formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof or any optical isomer thereof, mixture of optical isomers, including a racemix mixture, or any tautomeric form thereof together with a pharmaceutically acceptable carrier or diluent.
In another aspect, the present invention relates to a method for the treatment of diabetes, preferably Type 2 diabetes, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof, or of a composition according to the present invention.
In a still further aspect, the present invention relates to a method for the treatment of glycogen phosphorylase dependent diseases the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof, or of a composition according to the present invention.
In still another aspect, the present invention relates to a method for inhibition of glucose production from the liver, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof, or of a composition according to the present invention.
In still another aspect, the present invention relates to a method for the treatment or prophylaxis of obesity or appetite regulation, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof, or of a composition according to the present invention.
In still another aspect, the present invention relates to the use of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof for the preparation of a medicament.
Furthermore the present invention relates to the use of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt of prodrug or hydrate thereof for the preparation of a medicament for the treatment or prevention of diabetes, preferably Type 2 diabetes.
More particular the present invention relates to the use of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof for the preparation of a medicament for inhibiting the glucose production from the liver.
The present invention relates furthermore to the use of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof for the preparation of a medicament for inhibiting liver glycogen phosphorylase.
The present invention relates furthermore to the use of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof for the preparation of a medicament for the treatment or prophylactic of obesity or appetite regulation.
The present invention relates furthermore to the use of a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of hyperglycemia, hyperchloesterolemia, hyperinsulinemia, atherosclerosis, hyperlipidemia or hypertension.
The term xe2x80x9ctreatmentxe2x80x9d as used herein is intended to include prophylacit treatment.
In the structural formulas given herein and throughout the present specification, the following terms have the indicated meaning:
The term xe2x80x9coptionally substitutedxe2x80x9d as used herein means that the group in question is either unsubstituted or substituted with one or more of the substituents specified. When the group in question are substituted with more than one substituent the substituent may be the same or different.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
The term xe2x80x9cperhalomethylxe2x80x9d means trifluoromethyl, trichloromethyl, tribromomethyl, or triiodomethyl.
The term xe2x80x9cC1-8-alkylxe2x80x9d as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms such as e.g. methyl, ethyl, n-propyl, isoproyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, neopentyl, n-pentyl, n-hexyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1,2,2-trimethylpropyl and the like. The term xe2x80x9cC1-8-alkylxe2x80x9d as used herein also includes secondary C3-8-alkyl and tertiary C4-8-alkyl.
The term xe2x80x9cC2-8-alkenylxe2x80x9d as used herein alone or in combination represents a straight or branched hydrocarbon group containing from 2 to the specified number of carbon atoms and at least one double bond. Typical C2-8-alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-penten;yl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like.
The term xe2x80x9cC2-8-alkynylxe2x80x9d as used herein alone or in combination, represents a straight or branched hydrocarbon group containing from 2 to the specified number of carbon atoms and at least one triple bond. Examples of xe2x80x9cC2-8-alkynylxe2x80x9d groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
The term xe2x80x9cC3-8-cycloalkylxe2x80x9d as used herein represents a carbocyclic group having from 3 to 8 carbon atoms. typical C3-8-cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9cC1-8-alkoxyxe2x80x9d as used herein, alone or in combination, refers to the radical xe2x80x94Oxe2x80x94C1-8-alkyl where C1-8-alkyl is as defined above. Typical C1-8-alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term xe2x80x9cC1-8-alkylthioxe2x80x9d as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a lower alkyl group linked through a divalent sulphur atom having its free valence bond from the sulphur atom and having 1 to 8 carbon atom such as e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio and the like.
The term xe2x80x9cC1-8-alkoxycarbonylxe2x80x9d as used herein refers to a monovalent substituent comprising a C1-8-alkoxy group linked through a carbonyl group; such as e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tertbutoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.
The term xe2x80x9cphenyl-C1-8-alkylxe2x80x9d as used herein refers to a straight or branched saturated carbin chain containing from 1 to 8 carbon substituted with phenyl; such as e.g. benzyl, phenylethyl, 3-phenylpropyl and the like.
The term xe2x80x9cC1-8-alkylphenylxe2x80x9d as used herein refers to phenyl substituted by C1-8-alkyl as defined above.
The term xe2x80x9ccarbamoylxe2x80x9d as used herein refers to NH2C(O)xe2x80x94.
The term xe2x80x9ccarbonyl(C1-8)-alkylxe2x80x9d as used herein refers to carbonyl substituted by (C1-8)-alkyl as defined above.
The term xe2x80x9carylxe2x80x9d s used herein includes carbocyclic aromatic ring systems. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems.
The term xe2x80x9cheteroarylxe2x80x9d as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur; such as e.g. furyl, thienyl, pyrrolyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
Examples of xe2x80x9carylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d includes, but are not limited to phenyl, biphenyl, indene, fluorene, napthyl (1-naphthyl, 2-naphthyl), anthracene (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophene (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, oxatriazolyl, thiatriazolyl, quinazolin, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), oxaxolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isooxazolyl (isooxazo-3-yl, isooxazo-4yl, isooxaz-5-yl), isothiazolyl (isothiazo-3yl, isothiazo-4-yl, isothiaz-5-yl) thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), benzo[b]thiophenyl (benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl), 2,3-dihydro-benzo[b]thiophenyl (2,3-dihydro-benzo[b]thiophen-2-yl, 2,3-dihydro-benzo[b]thiophen-3-yl, 2,3-dihydro-benzo[b]thiophen-4-yl, 2,3-dihydro-benzo[b]thiophen-5-yl, 2,3-dihydro-benzo[b]thiophen-6-yl, 2,3-dihydro-benzo[b]thiophen-7-yl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (2-benzoxaxolyl, 3-benzoxazolyl, 4-benzoxazolyl, 5-benzoxaolyl, 6-benzoxazolyl, 7-benzoxazolyl), benzothiazolyl (2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carboazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 11,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-diydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), benzo[1,3]dioxole (2-benzo[1,3]dioxole, 4-benzo[1,3]dioxole, 5-benzo[1,3]dioxole, 6 -benzo[1,3]dioxole, 7-benzo[1,3]dioxole(, and tetrazolyl (5-tetrazolyl, N-tetrazolyl).
The present invention also relates to partly or fully saturated analogues of the ring systems mentioned above.
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
In another aspect, the present invetnion includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula (I, Ia or Ib) or a pharmaceutically acceptable salt or prodrug or hydrate thereof together with a pharmaceutically acceptable carrier or diluent.
Optionally, a pharmaceutical composition of the present invention may comprise a compound of formula (I, Ia or Ib) combined with one or more compounds.
Pharmaceutical compositions containing a compound according to the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19th Ed., 1995. The comnposiitons may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
Typical compositions include a compound of formula (I, Ia or Ib) or a pharmaceutically acceptable basic addition salt or prodrug or hydrate thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material, which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, saolt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethlcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the present invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
The route of administration may be any route, which effectively transports the active compound of formula (I, Ia or Ib) to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
For nasal administration, the preparation may contain a compound of formula I, Ia or Ib dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet which may be prepared by conventional tabletting techniques may contain:
The compounds of the present invention may be administered to a mammal, especially a human, in need of such treatment, prevention, elimination, alleviation or amelioration of the various diseases as mentioned above, e.g. hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlioidemia or obesity, and especially diabetes. Such mammals also include animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
The compounds of the present invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, per day may be used. A most preferably dosage is about 0.5 mg to about 250 mg per day. In chossing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
Generally, the compounds of the present invention are dispensed in unit dosage form comprising from about 0.05 to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.05 mg to about 1000 mg, preferably from about 0.5 mg to about 250 mg of the compounds of formula I, Ia or Ib admixed with a pharmaceutically acceptable carrier or diluent.
The present invention also encompasses prodrugs of a compound according to the invention which on administration undergo chemical conversion by metabolic processes being becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of a compound according to the present invention which are readily convertible in vivo into a compound according to the present invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985. The ester derivatives of formula I, Ia or IB could be suitable prodrugs.
The present invention also encompasses active metabolites of a compound according to the invention.
In a further aspect of the present invention a compound according to the invention may be administered in combination with further pharmacologically active substances e.g. other antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART agonists, NPY antagonists, MC4 agonists, orexin antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, xcex23 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, GLP-1, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR xcex2 agonists.
In a preferred embodiment of the present invention the antiobesity agent is leptin.
In another preferred embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another preferred embodiment the antiobesity agent is dexfenfluramine.
In still another preferred embodiment the antiobesity agent is sibutramine.
In a further preferred embodiment the antiobesity agent is orlistat.
In another preferred embodiment the antiobesity agent is mazindol or phentermine.
In a further aspect of the present invention a compound according to the invention may be administered in combination with further pharmacologically active substances e.g. other lipid lowering agents.
A compound according to the present invention may also be administered in combination with an antidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases, wherein insulin resistance is the pathophysiological mechanism. Suitable antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference, as well as orally active hypoglycaemic agents.
The orally active hypoglycemic agents preferably comprise sulphonylureas, biguanides, oxadiazolidinediones, thiazolidinediones, xcex1-glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S, which are incorporated herein by reference, insulin sensitizers, hepatic enzyme inhibitors, glucose uptake modulators, compounds modifying the lipid metabolism, compounds lowering food intake, PPAR and RXR agonists and agents acting on the ATP-dependent potassium channel of the xcex2-cells.
In a preferred embodiment of the present invention a compound according to the invention is administered in combination with insulin.
In a further preferred embodiment a compound according to the present invention is administered in combination with a sulphonylurea such as, e.g., tolbutamide, glibenclamide, glipizide and glicazide.
In another preferred embodiment a compound according to the present invention is administered in combination with a biguanidine such as, e.g., metformin.
In still another preferred embodiment a compound according to the present invention is administered in combination with a thiazolidinedione such as, e.g., troglitazone, ciglitazone, pioglitazone, rosiglitazone and the compounds disclosed in WO 97/41097 to Dr. Reddy""s Research Foundation, especially 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]-methyl]-2,4-thiazolidinedione.
In a further preferred embodiment a compound according to the present invention is administered in combination with an agent acting on the ATP-dependent potassium channel of the xcex2-cells such as, e.g,. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
Furthermore, a compound according to the present invention may be administered in combination with an antihypertensive agent. Examples of antihypertensive agents are xcex2-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and xcex1-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
Any novel feature or combination of features described herein is considered essential to this invention.
In the Method and Examples the following terms are intended to have the following, general meaning:
The present invention also relates to methods of preparing the above-mentioned compounds.
The preparation of the compounds according to the present invention can be realized in many ways. These methods comprise:
1a) Reacting a compound of formula II with a compound of formula III in a solvent such as acetone, DMF, THF, NMP, DMSO, CH2Cl2 with a base such as NaOH, LiOH, TEA, DMAP, K2CO3, sodium hydride, potassium tert-butoxide, or sodium tert-butoxide to form a compound of formula IV. 
A is O or S. Lg is a leaving group such as F, Cl, Br, I, NO2, -OSO2CH3 or -OTs.
R1, R2, R3 and R4 have the meanings set forth above. When R1, R2, R3, and R4 are labile groups e.g. acids or hydroxy they are protected as well known derivatives such as carboxylic esters, sulphonic esters, phosphoric esters, nitrile, amides, or cyclic anhydrides or cyclic amides or as e.g. ethers.
When A is  greater than CO the compound is made by Friedel Craft acylation. 
IIb and IIIb are reacted in a aprotic solvent such as CS2 with a Friedel Craft catalyst such as AlCl3, FeCl3, SnCl4 or ZnCl2 to make IVb as described in J.Org.Chem 48(13) 2281-2285 (1983) or Justus Liebigs. Ann. Chem. 220, 250 (1993). Both references are incorporated herein by reference.
When A is  greater than CR9R10 the reaction can be made by cross coupling or Grignard coupling. 
X is B(OH)2, Cl, Br, I, CIMg-, BrMg-, or IMg- as described in synthetic Commun. 11, 513 (1981), Tetrahedron 54(12), 2953-2966 (1998), J.Chem.Soc.Chem.Com. 3, 305-306 (1995), J.Amer.Chem.Soc. 18(42), 10220-10227 (1996) or J.Chem.Soc.Per.Trans. 1(6) 719-730 (1993) all incorporated herein by reference.
If A in IIc is a  greater than CO and X is H this reaction can be performed as a Friedel Craft coupling as described above, under Friedel Craft conditions described above.
R1, R2, R3, R4 and R8 have the meanings set forth above. When R1, R2, R3 and R4 are labile groups e.g. acids or hydroxy, they are protected as well known derivatives such as carboxylic esters, sulphonic esters, phosphoric esters, nitrile, amides, or cyclic anhydrides or cyclic amides or as e.g. ethers.
1b) Reacting a compound of formula V with a compound of formula VI in a solvent such as mentioned above with a base such as mentioned above to produce a compound of formula VII. 
A is O, S, or N and Lg, R1, R2, R3, and R4 have the meaning set forth above. Compounds of formula VII can be reduced by catalytic hydrogenation, H2, Pd/C, to form compound IV.
2a) Reacting compound of formula IV with a compound of formula VIII in a solvent such as acetone, DMF, THF, CH2Cl2 or NMP with TEA, NaOH, LiOH, DMAP, K2CO3, sodium tert-butoxide or potassium tert-butoxide as base to produce a compound of formula IX. 
wherein A, R1, R2, R3, R4, and R8 have the meaning set forth above.
2b) A compound of formula IX can be synthesised from the R8-CO2H and the amine IV by coupling with HOBt, EDAC and TEA in a solvent such as DMF, CH2Cl2 or NMP to produce compounds of formula IX.
A compound of formula IV can be reacted with a compound of formula X like Y-CH2R8, wherein Y is a leaving group such as Cl, Br, I, -OSO2CH3, or -OTs, to produce a compound of formula XI in a solvent such as acetone, DMF, DMSO, THF, NMP or CH2Cl2 with a base such as NaOH, LiOH, K2CO3, TEA, DMAP, sodium tert-butoxide, or potassium tert-butoxide. 
wherein A, R1, R2, R3, R4, and R8 have the meaning set forth above.
3a) Reacting a compound of formula (XIII), wherein A is O or S, and R2 and R3 have the meaning set forth above with a compound of the general formula (XII), wherein Su is a substrate and L is a linker to form a compound of the general formula (XIV): 
3b) Reacting a compound of formula (XIV) with a compound of formula (V) to form a compound of formula (XV), wherein A is O or S and Lg, L, Su, R2, R3, and R4 have the meaning set forth above or wherein A is C the AH group is CR6R7Br and Lg are Sn(Me)3 or B(OH)2 WO95/04277 (1995) or J.Am.Chem.Soc. 116, 11171-11172 (1994). 
3c) Reducing a compound of formula (XV) to form a compound of formula (XVI) and reacting this compound with R8-COOH to produce a compound of formula (XVII): 
3d) Cleavage of a compound of formula (XVII) by e.g. treatment with a strong acid to form a compound of formula (I), wherein A is O, S or CR6R7, R1 is carboxylic acid, and R2, R3, R4, and R5 have the meaning set forth above.
The substrate Su may be any insoluble or partially insoluble material, to which compounds may be covalently attached. Substrates may be selected from the group consisting of any kind of organic or inorganic polymeric or oligomeric compound. Preferably the substrate may be selected from the groups consisting of polystyrene, polyethylene glycol (PEG), polyethylene glycol attached to polystyrene, polyacrylamides, polyamides, polysaccharides and silicates. Depending on the type of substrate chosen, different types of solvents or protecting groups may be used.
The linker L is a molecule with at least two reactive sites, which permit its covalent attachment to other molecules or to a substrate. Either the bond of the linker to the substrate or the bond of the linker to other molecules attached to it or the linker itself must be cleavable upon selective exposure to an activator such as a selected chemical activator or other specific conditions, e.g. by treatment with a strong acid or by exposure to electromagnetic radiation or by metal catalysis;
The starting materials employed in the synthesis of the compounds from formula II, III, V, VI and VIII are either known or may be prepared in conventional manner from commercially available materials, e.g according to the methods described in the examples.
Other compounds of the general formula I can be prepared by the above strategy. A variety of functional groups can be introduced in the compounds prepared as outlined above by methods well known to those skilled in the art.
The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the present invention in diverse forms thereof.